3-keto-13beta-alkyl-17beta-acetyl-gona-4, 9-dienes and process



United States Patent 3,370,071 3-KETO-ISB-ALKYL-17p-ACETYL-GONA-4,9-DIENES AND PROCESS Arthur A. Patclrett, Cranford, and Thomas B.Windholz,

Westfield, N..l., assignors to Merck & Co., Inc., Rahway, N.J., acorporation of New Jersey No Drawing. Filed June 1, 1965, Ser. No.460,505 3 Claims. (Cl. 260397.4)

ABSTRACT OF THE DISCLOSURE The invention disclosed herein is concernedwith novel intermediate compounds useful in preparing novel steroidcompounds of the gonane series, novel steroid compounds prepared fromthe novel intermediate compounds, and novel processes for preparing theintermediate and steroid compounds of the gonane series.

compound is reacted with bromoacetamide thereby converting the17a-ethynyl su'bstituent to 17a-dibrorno-acetyl which upon reductionwith zinc dust and acetic acid is debrominated to form a l7a-acetylgroup; this 3-al-koxy- 13fl-alkyl-l7a-acetyl-gona-l,3,5 )-trien-17,B o1acetate is then reacted with lithium in liquid ammonia whereby thearomatic ring A is partially reduced accompanied by a simultaneousreduction and rearrangement at C-17 to form 3-alkoxy l3fl-alkyl-l7/3-(l-hydroxyethyD-gona-Z, 5 l0)-diene; hydrolysis of the last namedcompound with aqueous acetic acid, followed by reaction of the resulting3-keto-A intermediate with bromine in pyridine, and oxidation of the17-side chain hydroXyl with chromium trioxide produces 3-keto-l3fi-alkyll7fi-acetyl-gona-4,9- diene.

This invention also relates to novel intermediate compounds, more'particularly, 3-keto-13,/8-alkyl-17;8-(l-hydroxyethyl)-gon-5(l0)-enecompounds and 3-keto-1313- alkyl 17,8-(l-hydroxyethyl)-gona-4,9-dienecompounds, and to novel 3-keto-13,8-alkyl-l7/3-acetyl-gona-4,9-dienecompounds in which the alkyl group on the 13-carbon atom is lower alkylhaving not more than five carbon atoms, more particularly, methyl,ethyl, normal-propyl,

' normal-butyl, isobutyl, normal-pentyl, and isopentyl. The

butyl, isobutyl and isopentyl, and R is a lower alkyl radical,preferably methyl.

r 3,370,071 Patented Feb. 20, 1968 ice III

OAc O CH; IHOH R1 H J I l t. H

VII

CH: J=O

VIII

The novel compounds of this invention,3-keto-13fialkyl-l7B-acetyl-gona-4,9-diene compounds, have utility asprogestational agents and because of this property they may be used toregulate the estrus cycle in domestic animals and in cases of menstrualdisturbances may be used to re-establish the normal relationshipsbetween the anterior pituitary, ovary, and endometrium which are presentin a normal estrus cycle. They may also be used to syncronize the estruscycles of a herd or colony of domestic animals or to chronically supressestrus in domestic animals. When used for these purposes, the novelcompounds may be supplied together or in succession with an estrogenichormone.

Because of the progestrone-like effects of the novel compounds of thisinvention, they alfect the secretion of gonadot ropins and thus act toregulate ovulation and endometrial and placental development. Whencombined with estrogens or androgens, the novel compounds of thisinvention reduce fertility. The novel compounds of this invention alsohave utility in correcting disorders such as dysmenorrhea, amenorrhea,threatened abortion, endometriosis, and the like.

The novel compounds of this invention may be administered orally orparenterally and for this purpose a wide variety of oral or parenteraldosage forms may be used in which they may be present singly, or in amixture with another active ingredient, such as an estrogen. In thevarious dosage forms, they can be combined with an inert solid diluentor dissolved, dispersed, or suspended in a suitable liquid carrier. Whencombined with an inert solid diluent, they may 'be in suitable dosageunit form, more particularly in the form of a tablet, powder, capsule orthe like. When combined with a liquid diluent, the composition may be inthe form of a solution, emulsion, suspension or the like. The novelcompounds of this invention may also be formulated into an ointment,cream, lotion, or the like, which is suitable for topicaladministration, and in this form they may be combined with an additionalactive ingredient, such as an antibiotic, .germicide, or the like.

3 alkoxy 13B alkyl gona l,3,5(l)-trien-l7-one compounds are the startingmaterials for the synthesis of the novel intermediate compounds and thenovel 3-keto- 13,8-alkyl 17fi-acetyl-gona-4,9-diene compounds.

The first step of the synthesis of the 3-ket-o-l3fi-alkyl-17,8-acetyl-gona-4,9-diene compounds is the ethynylation of Compound Iin an alcohol solution containing dissolved acetylene and potassiummetal. For example, Compound I is added to a saturated acetylenesolution prepared by passing a stream of acetylene gas 'over the surfaceof a stirred solution of potassium in tertiary-amyl alcohol andanhydrous ethyl ether, which is maintained at a temperature of about 0C. until the solution is saturated with acetylene gas. After theaddition of Compound I is complete, acetylene gas is passed over thereaction mixture for tirom three to four hours while the temperature ismaintained at 0 C. and then for about eighteen hours while thetemperature is kept at room temperature. Ten percent aqueous ammoniumchloride solution is then added to the reaction mixture and thetertiary-amyl alcohol is removed by steam distillation.3-alkoxy-13fl-alkyl- 17a-ethynyl-gona-1,3,5(10)-trien-17fi-ol (Compound11) precipitates as the tertiary-amyl alcohol is distilled off and isremoved by filtration.

Compound II is acetylated in a second step to provide 3 alkoxy 13/3alkyl 17a ethynyl gona l,3,5(10)- trien-17/3-ol acetate (Compound III).Acetylation may be accomplished by dissolving Compound II in a solutionof acetic anhydride containing para-toluenesulphonic acid, distillingoif almost all of the acetic anhydride, adding water in an amountsufficient to convert the remaining acetic anhydride to acetic acid,adding sufficient aqueous sodium hydroxide solution to neutralize theacetic acid, extracting with ether, drying the ether extract overanhydrous sodium sulfate and evaporating the ether. The residue isCompound III.

The third step is the bromination of Compound III with N-bromoacetamide.Bromination is conveniently accomplished by adding N-bromoacetamide to asolution of Compound III in an organic solvent, such as tertiarybutylalcohol containing a small amount of water. The solution is stirred and3-alkoxy-13/i-alkyl-17a-dibromoacetyl-gona-l,3,5(10)-trien-l7-ol acetate(Compound IV) begins to crystallize from the reaction mixture Within afew minutes. After crystallization of Compound 1V is complete, water isadded, the reaction mixture is cooled to about 0 C. and Compound IV isremoved by filtration.

Compound IV is debrominated in a fourth step by the use of zinc dust andacetic acid. For example, by refluxing a stirred solution of Compound IVin acetic acid, containing sodium acetate, water, and zinc dust forabout fifteen minutes. The reaction mixture is filtered to remove anyunreacted zinc and the product is precipitated by the addition of waterand removed by filtration. The debrominated product is3-alkoxy-l3B-alkyl-l7u-acetyl-gona-L3, 5(l0)-trien-17,B-ol acetate(Compound V).

, Compound V is reduced with lithium or sodium in liquid ammonia in afifth step. For example, a solution of Compound V in an organic solvent,such as dry dioxane or dry tetrahydrofuran, is added to a solution oflithium in liquid ammonia. The reaction mixture is not cooled duringaddition and is allowed to stand with stirring for about one hour.Methanol is then added dropwise and after the addition of methanol iscomplete, additional lithium is added. The ammonia is allowed toevaporate and then water is added to the reaction mixture. The reactionproduct, 3 alkoxy 13/3 alkyl-l7fi-(1-hydroxyethyl)- gona-2,5(l0)-diene(Compound VI) separates out in solid form upon the addition of water.

The 3-enol ether structure of the A ring of Compound VI is rearranged ina sixth step to provide 3-keto-13flalkyl-17B-( l-hydroxyethyl)-gon5(10)-ene (Compound VII) by treatment with a weak acid, such as aceticacid or oxalic acid, in ethanol solution. For example, glacial aceticacid is added to a solution of Compound VI in absolute ethanol and afterthe addition is complete, a small amount of water is added. After thereaction mixture has stood for several hours, it is poured into asolution of sodium bicarbonate containing ice and allowed to stand untilthe reaction mixture is basic. The reaction mixture is extractedrepeatedly with benzene. The benzene extracts are washed with wateruntil the washings are only slightly basic, dried over anhydrouspotassium carbonate, filtered, and concentrated to dryness under reducedpressure. The residue is Compound VII.

As a seventh step, Compound VII is treated with bromine in pyridinesolution to provide 3-keto-l3fi-alkyl-17fl-(l-hydroxyethyl)-gona-4,9-diene (Compound VIII). For example, by addingone equivalent of bromine to a solution of Compound VII in pyridine,stirring the reaction mixture at room temperature for two hours, pouringinto ice Water and extracting with ether. The ether extract is washedwith water, dried over anhydrous sodium sulfate, and concentrated todryness under reduced pressure. The residue is3-keto-l3fl-alkyl-17,8(l-hydroxyethyD-gona-4, 9-diene (Compound VIII).

As a final step, Compound VIII is oxidized with chromium trioxide toprovide 3-keto-13fi-alkyl-l7fi-acetylgona-4,9-diene (Compound IX). Forexample, a solution of chromium trioxide in dilute sulphuric acidsolution is added to a solution of Compound VIII in acetone and when theoxidation reaction is complete, the reaction mixture is diluted withwater. Compound IX precipitates in crystalline form from the aqueousreaction mixture and is removed by filtration. Compound IX may bepurified by passing a benzene solution of Compound IX through a shortcolumn of alumina.

The 3-alkoxy 13,8 alkyl-gona-1,3,5 10)-trien-17-one compounds having8,8, 91 and hydrogen atoms may be prepared from known 3-alkoxy-138-alkyl-gona-1,3, 5(10),8,14-pentaen-17-one (Compound IX) by a knownprocedure whichis represented by the following series of reaction stepswherein the reactants are designated by chemical formulae in which R andR have the same significance as above:

The first step in the preparation of the 3-alkoxy-l3;8-alkyl-gona-l,3,5()-trien-17-0ne compounds is the catalytic hydrogenationof Compound IX in solution in a hydrocarbon solvent, such as benzene ortoluene, by the use of a catalyst, such as 2% palladised calciumcarbonate. The reaction may be conducted at room temperature and iscontinued until the theoretical amount of hydrogen has been absorbed.The hydrogenation product is 3-alkoxy 13p alkyl-gona 1,3,5(10),8tetraen-17-one (Compound X).

The second step is the rearrangement of the A doublebond of Compound Xto the A901) position by the treatment of Compound X with methanolichydrochloric acid. The rearranged product is 3-alkoxy-13B-alkyl-gona-L3,5(10),9(11)-'tetraen-17-one (Compound XI).

The A991) double-bond of Compound XI is hydrogenated as a third step.This may be accomplished by shaking an ethanol solution of Compound XIwith hydrogen in the presence of 10% palladised charcoal as a catalyst.The reaction is continued until no more hydrogen is absorbed. Thereaction product is 3-alkoxy-13B-alkylgona-1,3,5(10)-trien-17-one(Compound I).

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 2.3-meth0xy-13,8-is0pr0panol-g0na-1,3,5 (1 0 9 (11 )-tezraen-17-0ne A solution of 0.25 g. of 3-methoxy-l3B-isopropyl-gona-1,3,5(10),8-tetraen-17-one in 100 ml. of methanolic hydrochloric acid isrefluxed for forty-five minutes. The solution is then evaporated todryness under reduced pressure. The residue is3-methoxy-13B-isopropyl-gona-L3, 5(10),9(11)-tetraen-17-one and iscrystallized from methanol.

Example 3 .3-m eth oxy-I 3fi-isopropyl-g0na- 1,3,5(10) -trien-17-0ne Onegram of 3 methoxy-l3fi-isopropyl-gona-1,3,5(10), 9(l1)-tetraen-17-one in50 ml. ethanol containing 0.5 g. of 10% palladised charcoal is shakenwith hydrogen until no more hydrogen is adsorbed. The solution isfiltered and the alcohol is removed by evaporation under reducedpressure. The residue is 3-methoxy-13fl-isopropylgerm-1,3,5(10)-trien-17-one and is crystallized from methanol.

Example 4 .3-meth oxy-I 3 ,B-isopropyl-I 7 aethyny lgona- 1,3,5 10)-trien-1 75-01 Five 'grams of 3anethoxy-l3 3-isopropyl-gona-1,3,5 l0)-trien-l7-one are added to a saturated acetylene solution prepared bypassing a slow stream of acetylene-over the surface of a stirredsolution of potassium tertiary-amylate containing 5 g. of potassium insolution in 100 ml. of tertiary-amyl alcohol and 100 ml. of ether whilethe temperature is maintained at 0 C. After the addition is complete,acetylene gas is passed over the reaction mixture for four hours, duringwhich time the temperature of the reaction mixture is maintained at 0C., and then acetylene gas is passed" over the reaction mixture for aperiod of eighteen hours, during which time the temperature of thereaction mixture is maintained at room temperature. One hundred ml. of10% aqueous ammonium chloride solution are added to the reaction mixtureand the tertiaryamyl alcohol is removed by steam distillation. Thereaction product, 3-1methoxy-1SB-isopropyl-17a-ethynylgona- 1,3,5(10)-trien-17fi-ol, is removed by filtration and crystallized fromacetone.

Example 5 .-3-meth0xy-I 3p-is0pr0pyl-1 7 a-ethynylgona-1,3,5(10)-trien-17fl-0l acetate Five grams of3-methoxy-13/8-isopropyl-l7a-ethynylgona-1,3,5(10)-trien-17B-ol isallowed to stand overnight in solution in 50 ml. of acetic anhydridecontaining 2 g. of para-toluenesulfonic acid. The reaction mixture ispoured into 200 ml. of water and after one hour the reaction product isremoved by filtration and recrystallized from a solution of methanol andethyl acetate. The crystalline material is3-methoxy-13fi-isopropyl-lh-ethynylgona-1,3,5(10)-trien-17B-ol acetate.

Example 6.3-m ethoxy-]3/3-is0pr0pyl-1 7a-dibromoacetylgona-l ,3,5 (10-trien-1 718-01 acetate 1.6 grams of N-bromoacetamide is added to asolution of 2 g. of 3-methoxy-13,8-isopropyl-17a-ethynylgona-1,3,5(10)-trien-17, 3-ol acetate in 75 ml. of tertiary-butyl alcoholcontaining one ml. of water. The reaction product commences tocrystallize from the reaction mixture after the reaction mixture hasbeen stirred for a few minutes and after the reaction mixture is stirredfor one hour, 25 ml. of Water are added. The reaction mixture is cooledto 0 C. and the precipitate is removed by filtration and washed withmethanol. The precipitate is 3-met hoxy-13flisopropyl 17oz dibromoacetylgona- 1,3,5 (10)-trien-17/8-ol acetate and may berecrystallized from methylene chloride-methanol.

Example 7.3-meth0xy-13B-is0propyl-17a-acetylgona- 1,3,5 (10 -trien-1 78-0l acetate 2.75 grams of3-methoxy-13,8-isopropyl-17a-dibromoacetylgona-1,3,5(10)-trien-17fi-olacetate in solution in ml. of acetic acid containing 2.5 g. of anhydroussodium acetate, 10 ml. of water and 3.5 g. of zinc dust, is stirred forfifteen minutes on a steam bath. The unreacted zinc is then removed byfiltration and sufficient water is added to the reaction mixture tocompletely precipitate the reaction product. The precipitate is removedby filtration and recrystallized from methanol-ethyl acetate. Thereaction product is 3-methoxy-13fi-isoprop-yl-17u-acetylgona-1,3,5 10)-trien-17fi-ol acetate.

Example 8 .-3 -meth0xy-1 3 B-isopropy l-l 7,8-(1-hydr0xyethyl)-g0na-2,5(10)-diene,

A solution of 2 g. of3-methoxy-l3fi-isopropyl-17aacetylgona-1,3,5(10)-trien-17B-ol acetate in20 ml. of dry dioxane is added without external cooling to a solution ofone gram of lithium in 500 ml. of liquid ammonia. The reaction mixtureis stirred for one hour and 50 ml. of methanol are then added dropwiseover a period of fifteen minutes followed by the addition of 4 g. offinely divided lithium. After the lithium is added, the reaction mixtureis stirred for one-half hour and the ammonia is allowed to evaporate.Fifty ml. of water are added to the reaction mixture and the precipitatewhich is formed is removed by filtration. The precipitate is3-methoxy-13B- isopropyl-17fi-( l-hydroxyethyl)-gona-2,5 10)-diene.

3.2 milliliters of glacial acetic acid are added to a solution of mg. of3-methoxy-l3fi-isopropyl-17;8-( 1- hydroxyethyl)-gona-2,5(10)-diene in1.6 ml. of dioxane and 7.2 ml. of absolute ethanol. The reaction mixtureis allowed to stand at room temperature for five hours and thenpoured'into an aqueous solution of sodium bicar- 7 bonate containingice. This solution is allowed to stand until it is basic and thenextracted with benzene. The benzene extract is washed with water untilthe washings are slightly basic and then dried over anhydrous potassiumcarbonate, filtered and concentrated to dryness under reduced pressure.The residue is 3-keto-13,8-isopropyl-17B- (1-hydroxyethyl)-gon-5(10)-eneand is crystallized from ether.

Example 10.-3-ket0-13l3-is0pr0pyl-1 7,8-(1-hydr0xyethyl )gona-4,9-dieneOne molecular equivalent of bromine is added to 100 mg. of3-keto-13fl-isopropyl-17fi-(l-hydroxyethyl) gon-5(l0)-ene in solution infive ml. of pyridine. The reaction mixture is stirred for two hours atroom temperature and poured into ice water. The aqueous mixture isextracted with ether, the ether extract is washed with water, dried overanhydrous sodium sulphate, and the ether is removed by distillationunder reduced pressure. The residue is3-ket0-13B-isopropyl-17fi-(1-hydroxyethyl)- gona-4,9-diene.

A solution of 4.5 g. of chromium trioxide and 22 ml. of water containing4 ml. of concentrated sulphuric acid is added slowly to a solution of 10g. of 3-keto-13B-isopropyl-17/5'-(l-hydroxyethyl)-gona-4,9-diene in 40ml. of acetone. The reaction mixture is stirred during the addition andstirring is continued for 15 minutes after addition is complete. Onehundred milliliters of water are then added and the diluted reactionmixture is extracted with ether. The ether extract is dried overmagnesium sulphate and the ether is removed by distillation underreduced pressure. The residue is3-keto-l3/8-isopropyl-17p-acetylgona-4,9-diene and is crystallized fromacetone-hexane after chromatography on aluminum.

Example 12.-3-methoxy-13B-n0rmal butyl-l 7 a-ethynylgotta-1,3,5 lmien-175ml Five grams of 3-methoxy-l3fi-normal butyl-gona-1,3,5(10)-trien-17-one are added to a saturated acetylene solution preparedby passing a slow stream of acetylene over the surface of a stirredsolution of potassium tertiaryamylate containing 5 g. of potassium insolution in 100 ml. of tertiary-amyl alcohol and 100 ml. of ether Whilethe temperature is maintained at 0 C. After the addition is complete,acetylene gas is passed over the reaction mixture for four hours, duringwhich time the temperature of the reaction mixture is maintained at roomtemperature. One hundred ml. of aqueous ammonium chloride solution areadded to the reaction mixture and the tertiaryamyl alcohol is removed bysteam distillation. The reaction product, 3-methoxy-13;8normalbutyl-l7a-ethynylgona-1,3,5(10)-trien-17,B-ol is removed by filtrationand crystallized from acetone.

Example 1 3 .-3 -meth0xy-1 3,8-normal buty l-I7a-ethynylg0na-1,3,5(10)-trien-l 7&0! acetate Five grams of3-methoxy-13B-normal butyl-17a-ethynylgona-1,3,5(10)-trien-17{3-ol isallowed to stand overnight in solution in 50 ml. of acetic anhydridecontaining 2 g. of para-toluenesulfonic acid. The reaction mixture ispoured into 200 ml. of water and after one hour the reaction product isremoved by filtration and recrystallized from a solution of methanol andethyl acetate. The crystalline material is 3-methoxy-13fi-normalbutyl-17a-ethynylgo-na- 1,3,5 10)-trien-l7t3-ol acetate.

Example 14.3-methoxy-13B-n0rmal butyl-17fi-dibr0m0-acetylg0na-1,3,5(10)-trien-17B-0l acetate 1.6 grams of N-bromoacetamideis added to a solution of 2 g. of 3-methoxy-13fl-normalbutyl-l7ot-ethynylgona-1,

3,5(10)-trien-17fi-ol acetate in ml. of tertiary-butyl alcoholcontaining one ml. of water. The reaction product commences tocrystallize from the reaction mixture after the reaction mixture hasbeen stirred for a few minutes and after the reaction mixture is stirredfor one hour, 25 ml. of water are added. The reaction mixture is cooledto 0 C. and the precipitate is removed by filtration and washed withmethanol. The precipitate is 3-methoxy-13B- normalbutyl-17a-dibromoacetylgona-1,3,5( 10)-trien-l7,8- ol acetate and may berecrystallized from methylenechloride methanol.

Example I5.3-meth0xy-13 3-n0rm'al baly l-] 7 aacetylg0na-1,3,5(10)-trien-1 7,8-01 acetate Example 1 6.-3-meth0xy-1iii-normal bulyl-l7p- (1 -hydr0xyethyl) -gona-2,5 (1 0 -diene A solution of 2 g. of3-methoxy-l 3fi-normal butyl-17aacetylgona-l,3,5(10)-trien-17B-olacetate in 20 ml. of dry dioxane is added without external cooling to asolution of one gram of lithium in 500 ml. of liquid ammonia. Thereaction mixture is stirred for one hour and 50 ml. of methanol are thenadded dropwise over a period of fifteen minutes followed by the additionof 4 g. of finely divided lithium. After the lithium is added, thereaction mixture is stirred for one-half hour and the ammonia is allowedto evaporate. Fifty ml. of water are added to the reaction mixture andthe precipitate which is formed is removed for filtration. Theprecipitate is 3methoxy-13/3-normal butyl-17B- l-hydroxyethyl) -gona-2,5(10)-diene.

Example 1 7 .3 -ket0.1 3fi-n0rmal butyl-l 7 b- (1 -hydroxyethyl) -gon-5(1 0 -ene 3.2 milliliters of glacial acetic acid are added to asolution'of 160 mg. of 3-methoxy-l3fi-normal butyl-l7t3-(1-hydroxyethyl)-gona-2,5(10)-diene in 1.6 ml. of dioxane and 7.2 ml. ofabsolute ethanol. The reaction mixture is allowed to stand at roomtemperature for five hours and then poured into the aqueous solution ofsodium bicarbonate containing ice. This solution is allowed to standuntil it is basic and then extracted with benzene. The benzene extractis washed with water until the washings are slightly basic and thendried over anhydrous potassium carbonate, filtered and concentrated todryness under reduced pressure. The residue is 4-keto-13 8-norma1butyl-17fi-(l-hydroxyethyl)-gon-5(l0)-ene and is crystallized fromether.

Example 18.--3-keto-13{3-normal butyl-I 7B-(1-hydroxyethyl-g0na-4,9-diene One molecular equivalent of bromine is added to mg. of3-keto-l3fl-normal butyl-l7 3 (l hydroxyethyl)- gon-S 10)-ene insolution in five ml. of pyridine. The reaction mixture is stirred fortwo hours at room temperature andpoured into ice water. The aqeousmixture is extracted with ether, the ether extract is washed with water,dried over anhydrous sodium sulphate, and the ether is removed bydistillation under reduced pressure. The residue is 3-keto-l3fl-normalbutyl-l7fi-(1-hydroxyethyl)-gona-4,9-diene.

A solution of 4.5 g. of chromium trioxide and 22 ml. of water containing4 ml. of concentrated sulphuric acid is added slowly to a solution of 10g. of 3-keto-13fi-normal butyl-17fl-(l-hydroxyethyl)-gona-4,9-diene and40 ml. of acetone. The reaction mixture is stirred during the additionand stirring is continued for 15 minutes after addition is complete. Onehundred milliliters of water are then added and the diluted reactionmixture is extracted with ether. The ether extract is dried overmagnesium sulphate and the ether is removed by distillation underreduced pressure. The residue is 3-keto-135-normal-butyl-17B-acetyl-gona-4,9-diene and is crystallized fromacetone-hexane after chromatography on aluminum.

Example 20.3-meth0=xy-13,8-metlzyl-1 7 a-ethynyL gna-1,3,5 (1 0 -trien-17fl-ol Five grams of 3-methoxy-13B-methyl-gona-l,3,5(l0)- trien-17-oneare added to a saturated acetylene solution prepared by passing a slowstream of acetylene over the surface to a stirred solution of potassiumtertiary-amylate containing 5 g. of potassium in solution in 100 ml. oftertiary-amyl alcohol and 100 ml. of ether while the temperature ismaintained at 0 C. After the addition is complete, acetylene gas ispassed over the reaction mixture for four hours, during which time thetemperature of the reaction mixture is maintained at 0 C., and thenacetylene gas is passed over the reaction mixture for a period ofeighteen hours, during which time the temperature of the reactionmixture is maintained at room temperature. One hundred ml. of aqueousammonium chloride solution is added to the reaction mixture and thetertiary-amyl alcohol is removed by steam distillation. The reactionproduct, 3 methoxy 13B methyl 17a ethynylgona- 1,3,5 1O -trien-17 {3-01,is removed by filtration and crystallized from acetone.

Example 21.-3-m'ethoxy-13p-methyl-1 7a-ethynylgona-I ,3 ,5 (10) -trien-1713-01 acetate Five grams of 3-methoxy-l3fi-methyl-17a-ethynylgona-1,3,5 (l0)-trien-17,8-ol is allowed to stand overnight in solution in 50ml. of acetic anhydride containing 2 g. of para-toluenesulfonic acid.The reaction mixture is poured into 200 ml. of water and after one hourthe reaction product is removed by filtration and recrystallized from asolution of methanol and ethyl acetate. The crystalline material is 3methoxy-13Ii methyl 17a ethynylgona- 1,3,5 10) -trien-l7fl-ol acetate.

Example 22.--3-meth0xy-1 3 fl-m ethyl-1 7 a-d i bromoacetylg0nia-1,3,5(10 -trien-1 7 8-01 acetate 1.6 grams of N-bromoacetamide is added to asolution of 1 g. of 3-methoxy-l3/3-methyl-17a-ethynylgonia-1,3,5-(10)-trien 17,8-01 acetate in 75 ml. of tertiary-butyl alcoholcontaining one ml. of Water. The reaction product commences tocrystallize from the reaction mixture after the reaction mixture hasbeen stirred for a few minutes and after the reaction mixture is stirredfor one hour, 25 m1. of water are added. The reaction mixture is cooledto 0 C. and the precipitate is removed by filtration and washed withmethanol. The precipitate is 3-methoxy-13/imethyl 17adibromoacetylgonia-1,3,5(10)-trien-17p-ol acetate and may berecrystallized from methylene chloride-methanol.

Example 23.-3-methoxy-BB-metllyl-I 7a-alcetylgo m'a- 1,3,5 (10) -trien-1718-01 acetate 2.75 grams of3-methoxy-13,8-methyl-17a-dibromoacetylgona-l,3,5(10)-trien-17B-olacetate in solution in 100 ml. of acetic acid containing 2.5 g. ofanhydrous sodium acetate, 10 ml. of water and 3.5 g. of zinc dust, isstirred for fifteen minutes on a steam bath. The unreacted zinc is thenremoxed by filtration and suflicient water is added to the reactionmixture to completely precipitate the reaction product. The precipitateis removed by filtration and recrystallized from methanol-ethyl acetate.The reaction product is3-methoxy-13,8-methyl-17a-acetylgonal,3,5(10)-trien-17fl-ol acetate.

Example 24 .-3 -meth oxy-J 3 fl-metlty l-] 718- (1 -hydroxyethyl)-g0na-2,5 (10) -dien.e

A solution of 2 g. of3-methoxy-13/3-methyl-17a-acetylgona-1,3,5(10)-trien-17fl-ol acetate in20 ml. of dry dioxane is added without external cooling to a solution ofone gram of lithium in 500 ml. of liquid ammonia. The reaction mixtureis stirred for one hour and 50 ml. f methanol are then added dropwiseover a period of fifteen minutes followed by the addition of 4 g. offinely divided lithium. After the lithium is added, the reaction mixtureis stirred for one-half hour and the ammonia is allowed to evaporate.Fifty ml. of Water are added to the reaction mixture and the precipitatewhich is formed is removed by filtration. The precipitate is3-methoxy-13/i-methyl- 17/8-(1-hydroxyethyl)-gona-2,5( 10)-diene.

3.2 milliliters of glacial acetic acid are added to a solution of 160mg. of 3-methoxy-l3,8-methyl-17fl-(l-hydroxyethyl)-gona-2,5(10)-diene in1.6 ml. of dioxane and 7.2 ml. of absolute ethanol. The reaction mixtureis allowed to stand at room temperature for five hours and then pouredinto an aqueous solution of sodium bicarbonate containing ice. Thissolution is allowed to stand until it is basic and then extracted withbenzene. The benzene extract is washed with water until the washings areslightly basic and then dried over anhydrous potassium carbonate,filtered and concentrated to dryness under reduced pressure. The residueis 3-keto-13B-methyl-17B-(l-hydroxyethyl)-gon-5(10)-cue and iscrystallized from ether.

Example 26.-3-ket0-13fl-methyl-1 7fl-(1-hydr0xyethyl) gon-4,9-diene Onemolecular equivalent of bromine is added to mg. of 3 keto13B-methyl-17,8-(l-hydroxyethyl)-gon- 5(10)-ene in solution in five ml.of pyridine. The reaction mixture is stirred for two hours at roomtemperature and poured into ice water. The aqueous mixture is extractedwith ether, the ether extract is washed with water, dried over anhydroussodium sulphate, and the ether is removed by distillation under reducedpressure. The residue is 3- keto 13 fl-mbethyl-17fl-( l-hydroxyethyl)-gona-4,9-diene.

Example 2 7.3-ket0-13,8-methyl-1 7 fl-acetyl-gona-4,9-

diene A solution of 4.5 g. of chromium trioxide and 22 ml. of watercontaining 4 ml. of concentrated sulphuric acid is added slowly to asolution of 10 g. of3-keto-13/3-methy1-17,8-(l-hydroxyethyl)-gona-4,9-diene and 40 ml. ofacetone. The reaction mixture is stirred during the addition andstirring is continued for 15 minutes after addition is complete. Onehundred milliliters of water are then added and the diluted reactionmixture is extracted with ether. The extract is dried over magnesiumsulphate and the ether is removed by distillation under reducedpressure. The residue is 3-keto-13fi-methyl-17B-acetyl-gona- 4,9-dieneand is crystallized from acetone-hexane after chromatography onaluminum.

Various changes ad modifications may be made in carrying out the presentinvention without departing from the spirit and scope thereof. Insofaras these changes and modifications are within the. purview of theannexed claims, they are to be considered as part of our invention.

. 1 1 We claim: 1. A compound of the formula:

wherein R is a lower alkyl radical having not more than five carbonatoms.

2. 3 keto 13B methyl 17,8-(1-hydr0xyethyl)-gon- 3. 3 keto 13,6 isopropyl17p (1-hydroxyethyl)- gon-5( 10)-ene.

References Cited UNITED STATES PATENTS Perelman et al. 260397.4 Kinel eta1. 260-3974 Smith et a1. 260397.4 Fried et a1 260397.4 Alvarez 260397.3Fried et a1 260397.4

5 LEWIS GOTTS, Primary Examiner.

J. R. BROWN, Assistant Examiner.

